Enyne metathesis/Bronsted acid-promoted heterocyclization

Article abstract of DOI:10.1021/jo802582k

The "one-pot" synthesis of nitrogen heterocycles and an oxygen heterocycle by enyne metathesis and in situ cyclization is reported

Full text of DOI:10.1021/jo802582k

SCHEME 1. One-Pot Approach to Heterocycles: Enyne
Metathesis and Acid-Promoted Cyclization
Enyne Metathesis/Brønsted Acid-Promoted
Heterocyclization
Kyle P. Kalbarczyk and Steven T. Diver*
Department of Chemistry, UniVersity at Buffalo, the State
UniVersity of New York, Buffalo, New York 14260
diVer@buffalo.edu
ReceiVed December 1, 2008
SCHEME 2. Boc Deprotection Results in Cyclative
1,4-Hydroamination
The “one-pot” synthesis of nitrogen heterocycles and an
oxygen heterocycle by enyne metathesis and in situ cycliza-
tion is reported.
Due to their prominence in pharmaceuticals, heterocycles
continue to demand the attention of organic chemists. In
particular, rapid access to heterocycles from acyclic precursors
(heterocyclization) is an attractive goal. In our investigations
directed toward the end functionalization of 1,3-dienes B
obtained by enyne metathesis, we found that Brønsted acids
can be used to effect cyclization of simple diene precursors in
a “one-pot” reaction (eq 1 in Scheme 1). The net reaction results
in both cyclization and the addition of nitrogen and hydrogen
to the ends of the diene, so it can be described as a formal 1,4-
hydroamination. In this Note, we show the effectiveness of this
reaction as a heterocycle synthesis, for both dehydropiperidines
(tetrahydropyridines) and tetrahydropyrans. Since the diene
substrates are readily accessible by catalytic enyne metathesis,
a facile new route to heterocycle synthesis from alkynes is
provided through application of this methodology.
electrophilic activation (Ba¨ckvall reaction). In these cases,
reoxidation of the metal is required. Our group previously
showed that the single-step enyne metathesis preparation of 1,3-
cyclohexadienes could be efficiently joined with the Ba¨ckvall
reaction.2 If a hydrogen atom and a nitrogen nucleophile are
added to the ends of the diene, then the process is a net 1,4-
hydroamination. Intramolecular 1,4-hydroamination of 1,3-
dienes has been described by Hong and Marks with use of
lanthanide catalysts to prepare pyrrolidines.3 For several years,
our research group has been interested in the enyne metathesis
as a means to rapidly access 1,3-dienes of varied substitution
pattern. As a part of this program, we have been interested in
introducing heteroatom functionality contained in the alkene or
alkyne substrates. Our investigation was prompted by two
research goals: first, to probe the electrophilic reactivity of the
1,3-diene, and second, by our desire for a “one-pot” transforma-
tion to access heterocycles. Our study began with electrophilic
diene activation by a proton.
Transition metal-based methods are the most commonly used
methods for the cyclization of 1,3-dienes to form heterocycles.
Palladium(II) activation of 1,3-dienes results in the formation
of both nitrogen1a-d and oxygen1e-i heterocycles through
(1) Nitrogen Heterocycles: (a) Ba¨ckvall, J. E.; Nystro¨m, J. E. J. Chem.
Soc., Chem. Commun. 1981, 5, 9–61. (b) Ba¨ckvall, J. E.; Andersson, P. G. J. Am.
Chem. Soc. 1990, 112, 3683–3685. (c) Andersson, P. G.; Ba¨ckvall, J. E. J. Am.
Chem. Soc. 1992, 114, 8696–8698. (d) Riesinger, S. W.; Lofstedt, J.; Pettersson-
Fasth, H.; Ba¨ckvall, J.-E. Eur. J. Org. Chem. 1999, 3277–3280. Oxygen
heterocycles: (e) Ba¨ckvall, J. E.; Andersson, P. G. J. Am. Chem. Soc. 1992,
114, 6374–6381. (f) Koroleva, E. B.; Ba¨ckvall, J.-E.; Andersson, P. G.
Tetrahedron Lett. 1995, 36, 5397–5400. (g) Nilsson, Y. I. M.; Aranyos, A.;
Andersson, P. G.; Ba¨ckvall, J.-E.; Parrain, J.-L.; Ploteau, C.; Quintard, J.-P. J.
Org. Chem. 1996, 61, 1825–1829. (h) Itami, K.; Palmgren, A.; Ba¨ckvall, J.-E.
Tetrahedron Lett. 1998, 39, 1223–1226. (i) Verboom, R. C.; Persson, B. A.;
Ba¨ckvall, J.-E. J. Org. Chem. 2004, 69, 3102–3111.
Preliminary studies identified an acid-promoted cyclization
under conditions of Boc protecting group removal (Scheme 2).
(2) Middleton, M. D.; Peppers, B. P.; Diver, S. T. Tetrahedron 2006, 62,
10528–10540.
(3) (a) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002, 124, 7886–7887. (b)
Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 15878–
15892.
10.1021/jo802582k CCC: $40.75
Published on Web 02/09/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2193–2196 2193

TABLE 1. Acid Screening
TABLE 2. Nitrogen Heterocycles by the One-Pot Cyclization
Approacha
entry
acid
TFA
HCl
CSA
MeSO3H
TfOH
equiv time, h conversion,a
%
yield of 5,b
%
1
2
3
4
5
9.0
0.4
0.4
0.4
0.4
1
5
5
5
1
100
59
78
100
100
81
ND
ND
67
83
a Conversion determined by gc. b Isolated yield. ND
determined.
)
not
Exposure of diene E-4A4 to TFA/CH2Cl2 resulted in cyclization
with concurrent Boc protecting group removal. In the event,
excess TFA gave clean conversion to the nitrogen heterocycle
5, with no other products detected by tlc.
Having identified a simple acid-catalyzed cyclization of the
1,3-diene, we next investigated other Brønsted acids. These
studies were conducted as one-pot sequential tandem reactions,
using the diene generated in situ by enyne metathesis.5 Once
the metathesis was complete, the mixture of the 1,3-diene, excess
1-hexene, and Grubbs catalyst 1 was directly treated with the
indicated amount of acid and heating was continued at 40 °C
(Table 1). Excellent conversion and very good chemical yield
was obtained with a large excess of trifluoroacetic acid (TFA,
pKa 3.45 in DMSO). Other strong acids were screened to
decrease the amount of acid needed for cyclization. Anhydrous
HCl (pKa 1.8 in DMSO) gave incomplete conversion, possibly
due to loss of HCl over the protracted period of heating (entry
2). The organic-soluble camphorsulfonic acid (CSA) proved
effective in substoichiometric amount, though only 78% conver-
sion was found at 5 h reaction time (entry 3). Methanesulfonic
acid (pKa 1.6 in DMSO) gave higher conversion and a moderate
isolated yield. The disagreement between the conversion and
isolated yield is likely due to competing cationic polymerization
of the 1,3-diene during the extended reaction time. Last, 40 mol
% of triflic acid (pKa 0.3 in DMSO) was found to give good
conversions and high chemical yield of the cyclization product
(entry 5). The conditions in entry 5 were adopted as the standard
conditions. Triflic acid has been used to promote the intramo-
lecular hydroamination and hydroalkoxylation of alkenes by
Hartwig and co-workers.6 Triflic acid has also recently been
used by He and co-workers to effect an intermolecular 1,4-
hydroaminationof1,3-dienesemployingcarbamatenucleophiles.7,8
In the present study, very strong Brønsted acids were found to
promote the cyclization at substoichiometric amounts on the
crude intermediate diene obtained through enyne metathesis.
The one-pot enyne metathesis/heterocyclization was con-
ducted with catalytic triflic acid. The results are summarized in
a Reaction conditions: 1 (7-8 mol %), 1-hexene (9 equiv), CH2Cl2,
reflux, 1 h; addition of TfOH (0.4 equiv), reflux, 1 h. The ethylene and
propene runs were conducted for a period of 18 h with 5-10 mol % of
1 at room temperature, followed by addition of TfOH and reflux, 1 h.
Table 2. For the metathesis step, the 1-hexene runs were
conducted at 40 °C over 1 h; the ethylene runs were conducted
at rt over 18 h at 60-90 psig in a pressure tube. At the
conclusion of the metathesis, 40 mol % of triflic acid (TfOH)
was introduced and the reaction was stirred for 1 h. In this way,
the resulting heterocycle was obtained in 83% and 52% yield
(entries 1,2). R-Substitution adjacent to the nitrogen atom was
tolerated, and in the cases of hexene and propene (entries 3
and 4), 2,6-disubstituted dehydropiperidines were formed as
single diastereomers. For example, in the crude 1H NMR
spectrum of 9, one diastereomer was observed with no other
diastereomer seen within the limits of NMR detection.9 In the
ethylene case, the reaction proceeded with similar yield (entry
5). The chiral propargyl amino acid derivative 12 underwent
tandem reaction to afford the Fmoc-protected nitrogen hetero-
cycle with 2,6-disubstitution (entry 6). Last, the p-nosyl protect-
ing group could be employed in the sequence, giving the
corresponding nitrogen heterocycles (entries 7 and 8) in yields
comparable to that obtained with the tosyl group.
(4) In this case, only E-4A was detected. In the cross metathesis step with
simple alkenes, longer periods of heating give primarily the E-isomer: (a) Giessert,
A. J.; Diver, S. T. J. Org. Chem. 2005, 70, 1046–1049. (b) Clark, D. A.; Kulkarni,
A. A.; Kalbarczyk, K.; Schertzer, B.; Diver, S. T. J. Am. Chem. Soc. 2006, 128,
15632–15636.
(5) Similar studies were conducted with pure, E-4B: 4 equiv TFA promoted
the cyclization (100% conversion, 73% isolated). However, in the one-pot
reaction, 4 equiv of TFA did not result in full conversion of the intermediate
1,3-diene. Since excess alkene was still present, higher amounts of acid were
needed, see ref 8.
The relative stereochemistry of the 2,6-disubstituted hetero-
cycles was established by structural studies on dehydropiperidine
(7) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich Nicholas, W.; He, C.
Org. Lett. 2006, 8, 4175–4178.
(8) Interestingly, the He study (ref 7) reported intermolecular 1,2-hydroami-
nation of unactivated alkenes. In the present case, it is likely that some loss of
material is due to addition reactions to remaining 1-hexene.
(9) See the Supporting Information.
(6) (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471–1474. (b)
Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F.
Org. Lett. 2006, 8, 4179–4182.
2194 J. Org. Chem. Vol. 74, No. 5, 2009

SCHEME 3. Rationale for the Observed Selectivity
SCHEME 4. Formation of an Oxygen Heterocycle
9.9 Slow crystallization of 9 from ethanol produced X-ray quality
crystals, mp 93-95 °C. The n-butyl group and the phenyl moiety
were found to be cis-oriented, with the tosyl group occupying
the opposite side of the ring. On the basis of these data, we
have assigned the 2,6-cis relative stereochemistry in disubstituted
heterocycles 10 and 13. The observation of an axial arrangement
of the substituents at the 2- and 6-position, along with an axial
p-tosyl group, is consistent with observations made by others.10
The rationale for selective formation of diastereomer cis-9 is
presented in Scheme 3. Protonation at C4 would produce an
allylic carbocation that could undergo nucleophilic attack by
the nitrogen from either face, giving B and C. In B, the required
conformation adopted during C-N bonding positions the tosyl
group to develop strain with the R1 group. Alternatively, attack
on the other face of the allylic carbocation via C alleviates the
A1,3-like strain arising from the tosyl group and R1 in conforma-
tion B, thereby giving rise to diastereomer cis-D.10,11
SCHEME 5. NBS Electrophilic Activation (Eq 3) and
Spirocycle Formation (Eq 4)
The present method is distinct from metathesis methods used
for heterocyclic ring synthesis. There are many examples of
metathesis-based approaches to nitrogen heterocycles.12 In terms
of recent developments, the exchange of a carbocycle for the
heterocycle by ring rearrangement can be found in the inde-
pendent studies of Blechert13 and Mori.14 Metathesis-based
methods form the heterocyclic ring through C-C bond forma-
tion: for product A, the C3-C4 bond would be constructed by
ring-closing metathesis (Scheme 1). In this work, the enyne
metathesis is instead used to assemble the 1,3-diene for
electrophilic activation. In structure A (X ) N), the enyne
metathesis formally makes the C2-C3 and C4-C5 bond, whereas
the heterocycle is formed by C-N bonding promoted by the
Brønsted acid catalyst. As a result, the use of the enyne
metathesis/acid-promoted cyclization offers an alternative bond
connection to heterocycle synthesis. Importantly, the R1 and R2
elements are combined in an additive way from the respective
alkene and alkyne reactants.
The enyne metathesis/cyclization also provides tetrahydro-
pyrans by a similar 1,4-addition with use of substoichiometric
TFA (Scheme 4).15 In this case, additional steps are required
to protect the alcohol during the metathesis. Attempts to use
the free homopropargylic alcohols under standard enyne me-
tathesis conditions gave trace amounts of the conjugated dienes.
As a result, the alcohol was protected as the TBS ether. At the
conclusion of the metathesis, the Grubbs ruthenium carbene was
quenched16 by the addition of the polar isocyanide 18, and the
diene 19 isolated by chromatography. Deprotection of the TBS
group and cyclization with TFA gave the 2-substituted tetrahy-
dropyran 20 in good yield (62%, two steps).
(10) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 10, 1596–1598. (b) Hersh, W. H.; Xu, P.; Simpson,
C. K.; Grob, J.; Bickford, B.; Hamdani, M. S.; Wood, T.; Rheingold, A. L. J.
Org. Chem. 2004, 69, 2153–2163.
The cyclization could be induced by other electrophiles.
Position-selective activation of the 1,3-diene could be achieved
through bromonium ion formation (NBS). Intramolecular attack
by the nitrogen nucleophile and subsequent loss of proton
provides the 1,4-difunctionalized product 21 in good isolated
yield (eq 3, Scheme 5). The allylic bromide provides further
options for elaboration of dehydropiperidine 21 through C-C
bond formation. This electrophilic activation provides a means
(11) A1,3 strain was invoked in N-acyl piperidinone to explain diastereose-
lection during conjugate addition reactions: (a) Brown, J. D.; Foley, M. A.;
Comins, D. L J. Org 1988, 110, 7445–7447. For similar reasons, the N-tosyl
group in a piperidine ring system causes the 2-substituent to occupy an axial
position. See: (b) Craig, D. L.; McCague, R.; Potter, G.; Williams, M. R. V.
Synlett 1998, 55–57, and ref 10.
(12) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238.
(13) Piperidine: (a) Voigtmann, U.; Blechert, S. Synthesis 2000, 893–898.
Other ring-rearrangements: (b) Randl, S.; Lucas, N.; Connon, S. J.; Blechert, S.
AdV. Synth. Cat. 2002, 344, 631–633. (c) Imhof, S.; Blechert, S. Synlett 2003,
609–614. (d) Boehrsch, V.; Neidhoefer, J.; Blechert, S. Angew. Chem., Int. Ed.
2006, 45, 1302–1305.
(15) In this case, fewer equivalents of TFA were found to promote the
cyclization. Carbene 1 also promoted this metathesis.
(16) Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.;
Diver, S. T. Org. Lett. 2007, 9, 1203–1206.
(14) Kitamura, T.; Mori, M. Org. Lett. 2001, 3, 1161–1163.
J. Org. Chem. Vol. 74, No. 5, 2009 2195

petroleum ether) affording 115 mg of 5 as a clear colorless
amorphous solid in 83% yield. 1H NMR (500 MHz, CDCl3, ppm)
δ 7.69 (d, J ) 8.0 Hz, 2H), 7.23 (d, J ) 8.0 Hz, 2H), 5.34 (d, J )
1.5 Hz, 1H), 4.24 (d, J ) 1.5 Hz, 1H), 3.82 (dd, J ) 14.5, 6.5 Hz,
1H), 3.13 (ddd, J ) 14.5, 12.0, 4.5 Hz, 1H), 2.41 (s, 3H), 1.74-1.66
(m, 1H), 1.59 (m, 3H), 1.50 (s, 3H), 1.42-1.28 (m, 4H), 0.89 (t,
7.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3, ppm) δ 142.8, 138.7,
132.2, 129.3, 127.0, 122.0, 53.7, 38.5, 34.9, 28.3, 27.7, 23.2, 22.6,
21.4, 14.0; FT-IR (CH2Cl2, cm-1) 3026, 2967, 2921, 2861, 2730,
1920, 1683, 1604, 1499, 1453, 1387, 1348, 1229, 1157, 1104, 1045,
953, 900, 815, 775, 690, 637; ESI-MS molecular ion calculated
for C17H25O2NS 307.1606, found 308.1671 (M + 1), error -2.5
ppm.
to functionalize the allylic methyl group found in the products
of Table 2, above.
Making use of our recent cross metathesis method permitted
access to a spiro-fused dehydropiperidine. For access to the
spirocycle 23, we required disubstitution on the terminal position
of the 1,3-diene, which is normally difficult to achieve in cross
metathesis. Use of the geminally-substituted alkene methylene
cyclobutane17 gave rise to the novel spirocyclic heterocycle 23
(eq 4, Scheme 5). For this metathesis, a specialized Grubbs
catalyst 2218 was used so the metathesis could be conducted at
low temperature. The Brønsted acid-promoted cyclization proved
to be very fast, with complete reaction occurring within 15 min
at rt (eq 4, Scheme 5).
In summary, a new one-pot enyne metathesis, acid-promoted
cyclization has been developed. The reaction represents an
efficient means of heterocycle synthesis through the acid-
promoted end functionalization of an acyclic diene. This process
is very simple and uses readily available and inexpensive
Brønsted acids. In the case of dehydropiperidine heterocycle
synthesis, the reaction proceeds with high diastereoselectivity.
Further studies directed toward electrophilic activation to form
a variety of heterocyclic rings are ongoing in our laboratories.
6-Butyl-4-methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyri-
dine (9). Following the general procedure, 9 was obtained with
use of alkyne 8 (424 mg, 1.42 mmol) and 1-hexene (1.58 mL, 12.8
mmol) in 28 mL of dichloromethane (0.05 M). After removal of
the solvent, 9 was obtained as a crude yellow solid. The solid was
recrystallized by slow evaporation with ethanol affording 335 mg
of a white solid, mp 93-95 °C, in 65% yield. Crystals from this
sample were submitted for single crystal X-ray structure determi-
9
1
nation. Analytical TLC Rf 0.42 (1:4 ethyl acetate: hexanes); H
NMR (500 MHz, CDCl3, ppm) δ 7.75 (d, J ) 8.5 Hz, 2H), 7.37
(d, J ) 7.5 Hz, 2H), 7.29 (d, J ) 8.0 Hz, 4H), 7.23 (t, J ) 7.5 Hz,
1H), 5.35 (s, 1H), 5.24 (br d, J ) 7.0 Hz, 1H), 4.27 (br s, 1H),
2.43 (s, 3H), 2.20 (d, J ) 17.5 Hz, 1H), 1.81 (dt, J ) 17.5, 3.0 Hz,
1H), 1.70 (s, 3H), 1.22-1.15 (m, 2H), 1.05-0.93 (m, 2H),
0.86-0.77 (m, 2H), 0.70 (d, J ) 7.5 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3, ppm) δ 142.9, 140.7, 138.3, 129.5, 129.4, 128.0, 127.2,
127.0, 122.1, 54.4, 51.7, 35.2, 28.6, 28.2, 23.3, 22.3, 21.5, 13.8;
FT-IR (CH2Cl2, cm-1) 2967, 2927, 2861, 1598, 1493, 1460, 1387,
1341, 1282, 1157, 1098, 1045, 1012, 933, 887, 815, 690; ESI-MS
molecular ion calculated for C23H29O2NS 383.1914, found 406.1802
(M + Na), error -2.3.
Experimental Section9
General Procedure for Heterocycle Formation. To a dry 50
mL Schlenk tube was added a solution of alkyne (0.5 mmol) and
1-hexene (4.5 mmol, 9 equiv) in 10 mL of dichloromethane (0.05
M). The reaction vessel was then placed in a preheated oil bath at
45 °C. Grubbs’ catalyst 1 (0.035 mmol, 30 mg) was added and the
reaction mixture was allowed to stir until complete consumption
of alkyne, as detected by TLC analysis. At this time, approximately
180 µL (0.2 mmol) of a 1.13 M TfOH solution in dichloromethane
was added and the reaction was allowed to stir until consumption
of the intermediate 1,3-diene was complete, then the crude mixture
was concentrated in vacuo (rotary evaporator) to give the crude
products as oils.
Acknowledgment. The authors thank Dr. Mateusz Pitak
(SUNY Buffalo) for obtaining the X-ray structure of 9 and
William Karnofel for his assistance in the preparation of this
manuscript. This work was partially supported by the Petroleum
Research Fund (PRF AC-44202) and the NSF (CHE-601206).
6-Butyl-4-methyl-1-tosyl-1,2,3,6-tetrahydropyridine (5). Fol-
lowing the general procedure, the crude mixture was purified by
flash column chromatography with silica gel (1:6 ethyl acetate:
Supporting Information Available: Experimental proce-
dures and full characterization data for new compounds as well
as detailed crystallographic data for compound 9. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Use of methylene cyclobutane in enyne metathesis: Clark, D. C.;
Karnofel, W.; Basile, B.; Diver, S. T. Org. Lett. 2008, 10, 4927–4929.
(18) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.;
Schrodi, Y. Org. Lett. 2007, 9, 1589–1592. (b) Stewart, I. C.; Douglas, C. J.;
Grubbs, R. H. Org. Lett. 2008, 10, 441–444.
JO802582K
2196 J. Org. Chem. Vol. 74, No. 5, 2009